【作者】 朱晓光；

【导师】 仇晓菲；

【作者基本信息】 天津医科大学 ， 病理学与病理生理学， 2007， 硕士

【摘要】 结节性筋膜炎（nodular fasciitis, NF），又名假肉瘤性筋膜炎，是主要发生于皮下组织的结节性纤维性增生性病变。其病因和发病机制迄今未明。近年来，一些研究提供了其为“真性肿瘤”的分子遗传学依据，同时倾向认为其活跃增生的病变细胞是由纤维母细胞／肌纤维母细胞组成。转化生长因子β₁（Transforming growth factor-β₁, TGF-β₁）具有促进纤维母细胞增生和诱导肌纤维母细胞形成的作用。尚未检索到有关TGF-β₁在结节性筋膜炎中是否表达及是否参与病变发生发展的相关文献报道。目的：1．通过对结节性筋膜炎中的多种肌样标志物表达进行研究，旨在评估结节性筋膜炎中病变梭形细胞的免疫表达和肌纤维母细胞（肌样分化细胞）的构成。2．通过检测TGF-β₁及相关下游信号分子在结节性筋膜炎中的表达，了解TGF-β-1在结节性筋膜炎发病中的可能作用，并探讨其是否通过TGF-β₁／Smad途径传导信号，为将来利用TGF-β₁及其下游因子预防和治疗结节性筋膜炎提供参考依据。方法：本实验选择来自天津医科大学总医院和天津医科大学第二附属医院68例人结节性筋膜炎手术切除标本的病变区域及其病变周围区域为研究对象。采用免疫组化ABC三步法，分别检测（1）肌样标志物α-平滑肌肌动蛋白（α-SMA）、肌肉特异性肌动蛋白（MSA）、calponin和h-caldesmon的表达，（2）信号分子TGF-β₁、TGF-βRI、Smad2和Smad3的表达。运用SPSS13.0统计软件包进行数据处理，不同组别免疫表型的差异采用x²检验分析，相关关系采用Spearman等级相关分析法。结果：1．结节性筋膜炎中梭形细胞胞浆可见α-SMA、MSA及calponin阳性表达，呈弥漫或散在分布，阳性率分别为89.7％、86.8％和92.6％。所有病例h-caldesmon为阴性表达。2．TGF-β₁和TGF-βRI在结节性筋膜炎梭形细胞中可见阳性表达，阳性表达在富于细胞的增生区域尤为突出，阳性率分别为77.9％和80.9％；TGF-β₁和TGF-βRI在病变周围组织的梭形细胞中呈弱阳性表达，阳性率分别为30.9％和33.8％。TGF-β₁和TGF-βRI在结节性筋膜炎与病变周围组织中的表达差别有显著性意义（P＜0.05）。3．Smad2和Smad3在结节性筋膜炎梭形细胞的胞浆和胞核中呈不同程度阳性表达，阳性率分别为67.6％和61.8％；在病变周围组织梭形细胞中呈弱阳性表达，阳性率分别为25.0％和20.6％。Smad2和Smad3在结节性筋膜炎与病变周围组织中的表达差别有显著性意义（P＜0.05）。4．TGF-β₁和TGF-βRI阳性表达率之间有正相关性（P＜0.05，r_s=0.533）；TGF-βRI和Smad2阳性表达率之间有正相关性（P＜0.05，r_s=0.463）；TGF-βRI和Smad3阳性表达率之间有正相关性（P＜0.05，r_s=0.541）。结论：1．结节性筋膜炎中梭形细胞表达α-SMA、MSA和Calponin，其中以Calponin最敏感，但不表达h-caldesmon，表明结节性筋膜炎中部分增生的纤维母细胞发生肌样分化形成肌纤维母细胞；肌纤维母细胞是构成病变的重要成分，但可能不是主要成分。2．结节性筋膜炎的梭形细胞胞浆中TGF-β₁呈过表达，表明TGF-β₁可能以自分泌或旁分泌方式参与结节性筋膜炎的发病。TGF-β₁阳性表达在富于细胞的增生区域尤为明显，结合体外有关研究结果，推测TGF-β₁的自分泌或旁分泌可能涉及促进纤维母细胞增生和／或诱导肌纤维母细胞形成。3．TGF-βRI、Smad2和Smad3在结节性筋膜炎梭形细胞中的表达及阳性表达率之间的正相关性，为进一步证实TGF-β₁通过TGF-β₁／Smad传导通路参与结节性筋膜炎发病提供了形态学参考依据。更多还原

【Abstract】 Nodular fasciitis, also known, as subcutaneous pseudosarcomatous fasciitis, is amass-forming fibrous proliferation that usually occurs in the subcutaneous tissue. Theetiology and pathogenesis of nodular fascitiis are unknown. Recent cytogeneticstudies have demonstrated clonal chromosomal aberrations in a subset of the lesions,supporting nodular fisciitis as a neoplastic process. With the myofibroblast identifiedand characterized, it becomes apparent that the proliferating cells in nodular fasciitisare composed of fibroblasts and myofibroblasts. Transforming growth factor-β₁ isknown to stimulate fibroblast proliferation and to induce transdifferentiaton offibroblast towards myofibroblast, and has been localized immunohistochemically in awide variety of neoplastic and non-neoplastic tissue. However, there are no studies onthe expression and roles of TGF-β₁ in nodular fasciitis.Objectives:1. To examine the immunoexpression of myoid markers and evaluate themyofibroblastic phenotype in nodular fasciitis.2. To investigate expression and roles of TGF-β₁ and its related signaling moleculesin nodular fasciitis.Methods:The 68 paraffin embedded nodular fasciitis tissues, including the lesion tissues andthe tissues around the lesion, were studied immunohistochemically for the expressionof the following markers: （1） myoid markers: a- smooth muscle actin（a-SMA）,muscle special actin（MSA）, calponin and h-caldesmon; （2） signaling molecules:TGF-β₁, transforming growth factor-βreceptor typeⅠ（TGF-βRI）, Smad2 and Smad3.Chi-square test was used to evaluate the expression of TGF-β₁, TGF-βRI, Smad2 andSmad3 between the lesion tissues and the tissues around the lesion. Spearman rank correlation analysis was applied to assess their correlation in these samples.Results:1. The spindled cells in nodular fasciitis showed diffuse or focal immunoreactivityfor a-SMA, MSA and calponin, while h-caldesmon was absent. The positive ratesof a-SMA, MSA and calponin were 89.7％, 86.8％and 92.6％respectively.2. Strong expression of TGF-β₁ and TGF-βRI was demonstrated in the spindle cellsin nodular fasciitis, and week expression in the control. The staining for TGF-β₁and TGF-βRI was found prominently in spindle cell proliferation areas. Thepositive rates of TGF-β₁ and TGF-βRI were 77.9％and 80.9％respectively innodular fasciitis, while in the control the positive rates are 30.9％and 33.8％respectively. There was a significant difference between nodular fasciitis andperipheral zone reach statistical （P＜0.05）, both for the expression of TGF-β₁ andTGF-βRI.3. Strong expression of Smad2 and Smad3 was demonstrated in the spindle ceils innodular fasciitis, and week expression in the control. The positive rates of Smad2and Smad3 were 67.6％and 61.8％respectively in nodular fasciitis, while in thecontrol the positive rates were 25.0％and 20.6％respectively. There was asignificant differences between nodular fasciitis and the control（P＜0.05）, both forthe expression of Smad2 and Smad3.4. There was a positive correlation between the expression of TGF-β₁ and TGF-βRI（P＜0.05）, between the expression of TGF-β₁ and Smad2 （P＜0.05）, and betweenthe expression of TGF-β₁ and Smad3 （P＜0.05）.Conclusions:1. The immunoreactivity for a-SMA, MSA and calponin and absent of reactivity for h-caldesmon in spindle cell of nodular fasciitis indicate the existing ofmyofibroblastic phenotype in the lesion of nodular fasciitis, suggesting that somefibroblasts might be transdifferentiated to myofibroblasts in the development ofnodular fasciitis. Calponin is the most sensitive one for identifyingmyofibroblasts among the above markers. The results in this study alsodemonstrate that nodular fasciitis is not absolutely a lesion predominantlycomposed of myofibroblstic cells.2. TGF-β₁ overexpression noticed in nodular fasciitis might indicate that TGF-β₁participates in the development of nodular fasciitis. It may exert autocrine as wellas paracrine effects on promoting fibroblast proliferation and inducingmyofibroblast transdifferentiation.3. The increased expression of TGF-βRI、Smad2 and Smad3 and their positivecorrelations provide the further evidence that TGF-β₁ may, through TGF-β₁/Smadtransduction pathway, participates in the pathogenesis of nodular fasciitis.更多还原